Hepatitis C virus (HCV) plays a deleterious role in neurocognitive outcomes in HIV/HCV coinfected subjects. HCV is present in monocyte/macrophage (M/MF), which is known to traffic into the brain. In the brain, both HIV and HCV have been seen in astrocytes and microglia. Unlike HIV, individuals with untreated HCV may live with chronic viremia and not develop dementia. However, there are now increasing reports that HCV and in particular HIV/HCV coinfection are associated with cognitive impairment. We have preliminary data to show that M/MF from HIV/HCV coinfected individuals have a number of significantly elevated genes associated with chemotaxis and inflammation in HIV infection (CCL2, SN and OSM) and HCV infection (CXCL2, CXCL3, CXCL10, IL-8, CCL20). We also show that soluble products from M/MF of individuals with HCV or HIV/HCV cause neural cell death and apoptosis in human brain cultures. It is our overall hypothesis that the chronic viremia from HCV monoinfection and HIV/HCV coinfection activates the M/MF and this has an impact on neuropathogenesis leading to cognitive impairment. Our Specific Aims are: 1) To develop peripheral M/MF gene expression profiles from subjects with HCV and HIV/HCV with the goal of identifying activated pathways and significant genes/proteins involved;2) To characterize neural cell changes after treatments with M/MF supernatants from subjects with HCV and HIV/HCV using human brain cell aggregate or bilayer cultures, and specifically to identify soluble cytokine/chemokine profiles associated with each group and 3) To determine the level of neurocognitive impairment as measured by neuropsychological testing in HCV monoinfection and HIV/HCV coinfection and to correlate this with monocyte gene array profiles and supernatant neurotoxicity. We have combined the clinical expertise and well-characterized patient cohort of an HCV-based clinical hepatology group with the CNS expertise of an HIV basic neuroscience group to study the effects of chronic HCV and HIV/HCV infection on the CNS. PUBLIC HEALTH RELEVANCE: Approximately 1 in 4 Americans who are infected with HIV are also infected with the hepatitis C virus. Many people with hepatitis C or with both viruses have mental health and neurological problems, such as depression, poor concentration, or abnormal movements or sensations, but why they have these is not completely understood. This study compares monocyte/macrophages, specific immune cells, from these two groups of patients, with the aims of understanding their activities and whether they cause damage to normal brain cells in cell culture.